In the past year, the Cytotoxic Cell Studies Group has made significant progress in the investigation of the function and transcriptional control of human and mouse class I MHC receptors expressed on NK cells. We have identified and characterized probabilistic transcriptional switches in the human KIR genes, similar to the switches that we described in the murine Ly49 gene family. This indicates that probabilistic switches will likely be involved in many systems where genes are selectively activated in a subset of the cells in a given tissue. We are collaborating with Dr. J. Miller at the University of Minnesota, an expert on human NK cell differentiation and bone marrow transplantation to exploit our novel findings. This discovery has important implications for the control of stem cell differentiation, and may one day allow us to modify cell fate in differentiating systems such as bone marrow cultures. Our work has defined a novel paradigm for the selective activation of genes, and we are the pioneers in this area.In addition, we have continued to work on the structure and function of the Ly49 gene family in collaboration with Dr. Andrew Makrigiannis, a former post-doctoral fellow who has established an independent laboratory in Montreal. We have published two papers in Genes and Immunity this year on the nucleotide sequence of the Ly49 gene clusters in the 129/J and BALB/C mouse strains. This work provides the foundation for our continuing studies aimed at deleting the entire Ly49 gene cluster from mice. I am also collaborating with Dr. Makrigiannis on the generation of a complete set of peer-reviewed Ly49 molecule pages for the AfCS-Nature signaling gateway, and four of these have been accepted and published online this year. We have also collaborated with Dr. M. Lerman in the Laboratory of Immunobiology, NCI, to assist in the characterization of a gene knockout mouse that exibited impaired NK cell differentiation. This work has been submitted for publication. Finally, we are near the completion of a study in collaboration with Dr. H. Young in the Laboratory of Experimental Immunology that reveals a critical role for NF-kB p65 in the generation of the Ly49 repertoire.